Taking Ticagrelor? Frank, Proactive Conversations are Needed to Help With Adherence

Given the relatively high rate of premature discontinuation of ticagrelor (Brilinta; AstraZeneca) among ACS patients after PCI, physicians need to pay closer attention to bleeding, dyspnea, and arrythmias—the side effects that most commonly lead to nonadherence—and have honest conversations about cost and drug affordability, a new review paper advises.

“The biggest issues in practice are that there are these side effects, but they usually are quite manageable and can be handled by just reassuring the patients and following up and making sure that [they’re] not developing intolerable symptoms,” senior author Sandeep Das, MD, MPH, MBA (Florida Atlantic University, Boca Raton), told TCTMD. “And then the cost is something that we need to be more aware of and willing to have frank discussions with our patients about.”

Commenting on the paper for TCTMD, David Cohen, MD (University of Missouri-Kansas City School of Medicine), said “there's a lot of focus these days on trying to get patients to adhere to the things that we prescribe because if the pill never makes it from the bottle to the mouth of the patient, or from the pharmacy into the hand of the patient, it's not going to do a lot of good. We prescribe agents like ticagrelor because we think it's very beneficial for preventing some pretty serious events, so I think that understanding all the issues that can lead to noncompliance or nonadherence is important.”

Side Effects and Cost

Published online ahead of the May 21, 2019, issue of the Journal of the American College of Cardiology, Das along with lead author Sameer Arora, MD (University of North Carolina School of Medicine, Chapel Hill), and colleagues summarize the available evidence from studies including PLATO, PEGASUS-TIMI 54, SOCRATES, and EUCLID to show that the main drivers of premature drug discontinuation, which occurs in about one-quarter of patients, are bleeding complications, dyspnea, and conduction abnormalities.

The consequence of bleeding is “a little bit self-evident,” Das said. “The drug is a very potent antiplatelet agent, and a necessary consequence of that if you're decreasing thrombosis is you're going to increase bleeding.”

On the other hand, he continued, the mechanism behind the observed increased incidence of dyspnea “is not entirely clear. It was postulated to be adenosine-mediated, but that may or may not be the case. There's some conflicting data on that. But it definitely leads some patients to develop shortness of breath and to discontinue taking the drug.” The cardiac rhythm abnormalities also might be adenosine-mediated, he said.

Another hurdle both clinicians and patients must face is that ticagrelor “can be a very expensive drug,” Das said, especially compared with clopidogrel, which has been shown to have a less potent antiplatelet effect but as a generic is “quite a bit less expensive.”

Cohen agreed that physicians can do better about handling these issues. “The challenge for something like ticagrelor is that physicians are rarely aware of all the subtleties of the different insurance plans that our patients may have, whether it be Medicare or private insurance or uninsurance, and also are just not that aware of the different programs that exist from the manufacturers with coupons—programs that would give them free access to the care,” he said, noting that social workers are often relied on to bridge these gaps. “Most physicians are aware of [ticagrelor’s cost] to some degree and try to have some discussion of that with the patients because if the [patient can’t afford ticagrelor], it's far better for them to then have a prescription for generic clopidogrel that they can afford than take neither of those two.”

Alternative Affordable Options

In his experience, Cohen said he sees a lot of patients coming back after paying for the first prescription and asking for assistance with cost-lowering. “We do a number of things in our daily practice that are not well tested to try and deal with this,” including switching patients to clopidogrel before they leave the hospital or after the first month of ticagrelor treatment at home, he explained. “And then after their first month, [we] have a more formal discussion about, can they afford this or do we need to switch it at that point.”

Physicians should step back and realize that patients are often taking multiple drugs, many of which can be expensive on their own or unaffordable when new prescriptions are added on. “We don't want them deciding to pay the rent, to pay the food bill, or to take [their] life-prolonging medications,” Cohen said.

We don't want them deciding to pay the rent, to pay the food bill, or to take [their] life-prolonging medications. David Cohen

A switching protocol, which has shown success in recent studies, is definitely an option, Das said, “but it's a little trickier than it may at first seem, specifically with the timing. Clopidogrel is a different drug than ticagrelor so you have to be careful not to leave patients a window where they are under-covered by antiplatelet therapy, so the timing of loading a clopidogrel dose [and] timing it related to stopping your ticagrelor needs to be done with a little bit of care.”

Nonetheless, he said this is done “fairly routinely” at his institution. “It's a very reasonable strategy; probably the most common reason we do it is cost. The other side effects, like the dyspnea, [are] usually self-limited and mild, and it's pretty uncommon that we have to stop for that, but cost is the big one.” Das said the key to preventing a potentially unsafe situation is having an up-front conversation with the patient, “especially because patients may be embarrassed or uncomfortable to call back to their physician and say, ‘I can't afford it.’”

Many open questions remain regarding patient behavior when it comes to nonadherence, said Cohen. He cited the ARTEMIS trial, which indicated modest improvement in adherence with copay vouchers but showed that some patients don’t even use coupons, for unknown reasons. “I think that we do need to explore better ways of making that work even better,” he said. “And then I think we need to understand at some level the safety of these de-escalation protocols that people are using, and we use without strong justification for them. Is it okay—and at what time—to completely switch them to clopidogrel?”

Ultimately, physicians need to spend more time thinking about compliance and take a more proactive stance on preventing nonadherence. “We just don't do it that well, and when patients come back to us in clinic, I have to say that we are busy these days with just the business of medicine and dealing with whatever symptoms they are having or other sorts of things, that very often issues of whether they are actually taking the medications that are on their medication list don't get discussed very much, unless the patient brings it up,” Cohen said.

“Nonadherence to antiplatelet therapy represents a prevalent and potentially preventable barrier to optimal secondary prevention of cardiovascular events,” the authors conclude.